Our group studies cell death/proliferation signals in relation to development and disease, particularly in cancer of pigment cells (melanoma) and tumors of childhood. We attempt to understand critical models of cell homeostasis with a goal of molecular targeted therapy as well as prevention of melanoma and other human cancers.
We study detailed biology of melanocytes as a means of identifying pathways which drive melanoma in man. These studies include examination of the mechanisms underlying growth/survival of benign moles, the majority of which contain oncogenic mutations in either BRAF or N-Ras and appear to represent pre-malignant lesions. We also examine melanocyte death within hair follicles, a process which is associated with hair graying. Specific pathways have been identified which link hair graying to melanocyte and melanoma survival, and offer potential leads for novel therapies. Other studies focus on cell-cell communication pathways which modulate melanocytic responses to environmental cues. These studies include construction of oncogene-transformed melanocytic cell lines which exhibit growth factor independence and mimic human melanoma in a genetically controlled manner.
Malignant transformation of melanocytes produces one of the most treatment resistant malignancies in man. We have identified a transcriptional network which regulates melanoma cell survival and proliferation as well as melanocyte differentiation during development. Using diverse methods including mouse models, human tumor expression arrays, and cellular assays, we examine mechanisms through which melanoma cells evade death, with the goal of improving therapy. Studies include preclinical and clinical analyses of novel melanoma treatments.
Mitf is a helix-loop-helix factor homologous to Myc. Its mutation produces absence of melanocytes and severe abnormalities in osteoclasts, the cell responsible for bone mineral resorption. Mitf mutations occur in humans with the pigmentation/deafness condition Waardenburg Syndrome. Mitf acts as a master regulator of melanocyte and osteoclast development and is targeted by several critical signaling pathways. Recently, members of the Mitf family have been discovered as oncogenes in a variety of human malignancies, particularly sarcomas and renal carcinomas of childhood. Their roles in cancer as well as strategies to target them therapeutically are under active investigation.
Skin cancer, including melanoma, is in principal among the most preventable of human cancers. The pathways impacted by UV exposure to skin are incompletely understood, and simultaneously evoke damaging (mutational) and protective (tanning) responses. We study both of these processes in animal models as well as human skin, in order to understand the key biochemical and signaling pathways and develop strategies to manipulate in a medically beneficial fashion.